Josine Min | 17-01-2007| Generalised Osteoarthritis: from Mendelian Disorder to Complex Disease
Osteoarthritis (OA) is a prevalent and complex disorder with a high hereditary probability. Previous genetic research into OA has yielded several common gene variants contributing to joint specific OA phenotypes. Only a few studies allowed an examination of multiple joint sites in the patients included. In this thesis, we have focused, on the identification and investigation of OA susceptibility of rare and common generalised OA (GOA) in family based studies and common OA in the population. We investigated previously reported relationships between two candidate genes (FRZB and MATN3) with OA in a random sample from the population-based Rotterdam study and in siblings from the Genetics Osteoarthritis and Progression (GARP) study. A functional variant in FRZB indeed associates to OA but this seems not confined to hip only. Associations of MATN3 variants suggest that genetic variation in this gene determines susceptibility to spinal disc degeneration and OA of the first carpometacarpal joint. Different linkage areas were identified for early and late onset GOA. We mapped a major locus for OA at multiple joint sites on 14q32.11 in middle aged siblings from the GARP study and on 2q33.3 in seven early onset families. From our studies so far, DIO2, IDH1 and NRP2 may be new OA loci.